Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells

Background-Prostacyclin has proved to be a beneficial treatment for patient s with severe pulmonary hypertension. We postulated that the response may r eflect, at least in part, inhibition of pulmonary artery smooth muscle cell (PASMC) growth. Methods and Results-Human PASMCs were derived from distal (<1-mm external d iameter, n=8) and proximal (>8-mm external diameter, n=12) pulmonary arteri es obtained at transplant surgery and pneumonectomy. The effects of the sta ble prostacyclin analogues on [methyl-H-3]thymidine incorporation and cell proliferation were investigated by using immunohistochemically characterize d cells. Distal cells proliferated faster than did proximal PASMCs and disp layed a distinct sensitivity to cicaprost and iloprost. Both analogues inhi bited thymidine uptake over 24 hours (20% to 60%, P<0.001; n=8) and abolish ed stimulation of DNA synthesis by platelet-derived growth factor-BB (10 ng /mL) in distal but not proximal cells. The inhibitory effect of cicaprost w as mimicked by isoproterenol (10(-5) mol/L), forskolin (10(-5) mol/L), and dibutyryl cAMP (5x10(-4) mol/L) and was potentiated by the phosphodiesteras e inhibitor 3-isobutyl-1-methylxanthine (5 x 10(-5) mol/L). Cicaprost (10(- 10) to 10(-6) mol/L) inhibited the proliferation of PASMCs, which had been stimulated with either platelet-derived growth factor-BB or serum, and incr eased cAMP production. These effects were potentiated by 3-isobutyl-1-methy lxanthine and attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyade nosine (10(-5) to 10(-4) mol/L). Conclusions-Cicaprost and iloprost inhibit DNA synthesis and proliferation to a greater extent in distal compared with proximal human PASMCs, acting a t least in part via a cAMP-dependent mechanism. The results are consistent with the hypothesis that prostacyclin analogues inhibit vascular remodeling in pulmonary hypertension and demonstrate heterogeneity among human PASMCs .